GSK3-TIP60-ULK1 Signaling Pathway Links Growth Factor Deprivation to Autophagy
GSK3-TIP60-ULK1 Signaling Pathway Links Growth Factor Deprivation to Autophagy
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GSK3-TIP60-ULK1 信号通路将生长因子剥夺与自噬联系起来
DOI：
10.1126/science.1217032
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发表时间：
2012-04-27
期刊：
影响因子：
56.9
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
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作者：
Lin, Shu-Yong;Li, Terytty Yang;Lin, Sheng-Cai
乙酰化和自噬自噬允许细胞在必要时消化自己的成分以在压力条件下生存。Lin等（第477页）和Yi等（第474页）分别描述了哺乳动物细胞和酵母中的信号传导机制，通过该机制，自噬被蛋白质乙酰化调节。在缺乏血清的哺乳动物细胞中，乙酰转移酶TIP 60通过蛋白激酶GSK 3（糖原合成酶激酶3）的磷酸化而被激活。TIP 60的靶点似乎是一种对自噬调节至关重要的蛋白激酶ULK 1。这种激活途径是在没有血清的情况下自噬所必需的，但在缺乏葡萄糖的细胞中自噬不需要。在缺乏氮的酿酒酵母中，发现了另一种乙酰化机制。饥饿导致组蛋白乙酰转移酶Esa 1的激活，它使自噬机制的关键组分Atg 3乙酰化，从而增加了它与另一种自噬蛋白Atg 8的相互作用。信号通路参与细胞对血清饥饿的反应，但不参与葡萄糖饥饿。在后生动物中，细胞依赖于细胞外生长因子来维持能量平衡。我们发现，糖原合成酶激酶-3（GSK 3）在缺乏生长因子的细胞中默认去抑制时，通过磷酸化TIP 60-Ser 86激活乙酰转移酶TIP 60，从而直接乙酰化并刺激自噬所需的蛋白激酶ULK 1。经工程改造以表达不能被GSK 3磷酸化的TIP 60 S86 A的细胞不能经历血清剥夺诱导的自噬。ULK 1的乙酰化缺陷突变体未能拯救ULK 1 −/−小鼠胚胎成纤维细胞中的自噬。细胞使用从GSK 3到TIP 60和ULK 1的信号传导来调节缺乏血清而非葡萄糖时的自噬。这些发现揭示了整合蛋白磷酸化和乙酰化的激活途径，将生长因子剥夺与自噬联系起来。
Acetylation and Autophagy Autophagy allows cells to digest their own components when necessary to survive stressful conditions. Lin et al. (p. 477) and Yi et al. (p. 474) describe signaling mechanisms in mammalian cells and yeast, respectively, by which autophagy is regulated by protein acetylation. In mammalian cells deprived of serum, the acetyltransferase TIP60 was activated by phosphorylation by the protein kinase GSK3 (glycogen synthase kinase 3). TIP60's target appeared to be a protein kinase central to autophagy regulation, ULK1. This activating pathway was required for autophagy in the absence of serum, but was not needed for autophagy in cells deprived of glucose. In the yeast Saccharomyces cerevisiae starved of nitrogen, another acetylation mechanism was uncovered. Starvation led to activation of the histone acetyltransferase Esa1, which acetylated the protein Atg3, a key component of the autophagy machinery, thus increasing its interaction with another autophagy protein, Atg8. A signaling pathway is involved in cellular responses to serum starvation but not glucose starvation. In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser86, which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60S86A that cannot be phosphorylated by GSK3 could not undergo serum deprivation–induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1−/− mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.